Particulate products are of great interest for pharmaceutical applications, where there is a need to obtain particles of reproducible, preferably small, size and shape within a narrow size range. These physical criteria are important because the bioavailability of some pharmaceuticals is dependant on the size of the particles. Similarly, bioavailability may be adjusted by coatings (ie, encapsulation) or dispersion (eg, in a polymer matrix, particularly biodegradable polymers).
There are a number of dense gas techniques which have been used in the micronisation of particles. The two techniques particularly relevant to the present invention are Rapid Expansion of Supercritical Solutions (RESS) and Particles from Gas Saturated Solutions (PGSS).
The RESS process involves the material of interest being dissolved in a supercritical fluid solvent under pressure, and precipitating the solute by depressurising the solution across a nozzle.
The PGSS process involves applying a dense gas under pressure to a molten material. The dense gas dissolves in the material of interest to form a solute saturated solution, and the resulting liquid phase is sprayed through a nozzle into a vessel of lower pressure, which results in the dense gas being vaporised, leaving behind fine particles of the desired material. A typical apparatus for this process is illustrated schematically in FIG. 1 and described in more detail below. The PGSS process is discussed by Ker{hacek over (c)} et al in International Journal of Pharmaceuticals, Vol 182, 1999, 33-39. Since the PGSS process involves first heating the material of interest to its melting point, it is therefore limited to materials which do not thermally degrade below their melting point (ie are not thermally labile). However, as some materials experience a melting point depression in the presence of a dense gas, they may be used in the PGSS process if the dense gas depresses their melting point below the thermal degradation point. Of course, with some substances, these temperature points are not precise especially where the substance exists in different morphologies. Thus, the PGSS process has been found to have limited applications.
Another disadvantage of the PGSS process is that the viscosity of the solution being sprayed, while less than the viscosity of the molten solute, is still at a level that can cause the nozzle to block.
One known formulation method (which may be used, for example, for delayed release formulations) is to spray a molten pharmaceutical (or material of interest) into a solution of a sustained release compound (such as stearate) at increased temperature and pressure. This results in the newly formed particles of the pharmaceutical being coated in the stearate (or other similar compound) for delayed release or other applications. The utility of this method for pharmaceutical applications is restricted to the few pharmaceutical substances known to melt without decomposing.
Co-formulation of pharmaceuticals has also been proposed for increased efficacy or new applications. These may however be difficult to prepare, particularly if melting a compound so as to mix it with another partly decomposes it.
In attempting to overcome some of those difficulties and limitations, it has surprisingly been found that some compounds exhibit a melting point depression when exposed to a dense gas, which permits use of a dense gas process with such compounds. This process can be used with substances otherwise considered unsuitable given their melting point under normal conditions.